View source for Fructose 1,6-bisphosphatase

{{Short description|Class of enzymes}}
{{cs1 config|name-list-style=vanc}}
{{infobox protein
| Name = fructose-1,6-bisphosphatase 1
|caption= Fructose-1,6-bisphosphatase and its fructose 2,6-bisphosphate complex. Rendered from PDB [http://www.rcsb.org/pdb/explore/explore.do?structureId=3FBP 3FBP].
|image = Fructose-1.6-bisphosphatase-pdb-3FBP.png
| width = 200
| HGNCid = 3606
| Symbol = FBP1
| AltSymbols = FBP
| EntrezGene = 2203
| OMIM = 229700
| RefSeq = NM_000507
| UniProt = P09467
| PDB = 
| ECnumber = 3.1.3.11
| Chromosome = 9
| Arm = q
| Band = 22.3
| LocusSupplementaryData = 
}}
{{Infobox protein family
| Symbol = FBPase
| Name = Fructose-1-6-bisphosphatase
| image = PDB 1bk4 EBI.jpg
| width = 
| caption = crystal structure of rabbit liver fructose-1,6-bisphosphatase at 2.3 angstrom resolution
| Pfam = PF00316
| Pfam_clan = CL0171 
| InterPro = IPR000146
| SMART = 
| PROSITE = PDOC00114
| MEROPS = 
| SCOP = 1frp
| TCDB = 
| OPM family = 
| OPM protein = 
| CAZy = 
| CDD = 
}}
{{Infobox protein family
| Symbol = FBPase_2
| Name = Firmicute fructose-1,6-bisphosphatase
| image = 
| width = 
| caption = 
| Pfam = PF06874
| Pfam_clan = CL0163 
| InterPro = IPR009164
| SMART = 
| PROSITE = 
| MEROPS = 
| SCOP = 
| TCDB = 
| OPM family = 
| OPM protein = 
| CAZy = 
| CDD = 
}}
{{Infobox protein family
| Symbol = FBPase_3
| Name = Fructose-1,6-bisphosphatase
| image = 1umg4.jpg
| width = 
| caption = crystal structure of fructose-1,6-bisphosphatase
| Pfam = PF01950
| Pfam_clan =  
| InterPro = IPR002803
| SMART = 
| PROSITE = 
| MEROPS = 
| SCOP = 1umg
| TCDB = 
| OPM family = 
| OPM protein = 
| CAZy = 
| CDD = 
}}
The enzyme '''fructose bisphosphatase''' (EC 3.1.3.11; systematic name '''<small>D</small>-fructose-1,6-bisphosphate 1-phosphohydrolase''') catalyses the conversion of [[fructose-1,6-bisphosphate]] to [[fructose 6-phosphate]] in  [[gluconeogenesis]] and the [[Calvin cycle]], which are both [[Anabolism|anabolic pathways]]:<ref name="pmid2159755">{{cite journal | vauthors = Marcus F, Harrsch PB | title = Amino acid sequence of spinach chloroplast fructose-1,6-bisphosphatase | journal = Archives of Biochemistry and Biophysics | volume = 279 | issue = 1 | pages = 151–7 | date = May 1990 | pmid = 2159755 | doi = 10.1016/0003-9861(90)90475-E }}</ref><ref name="pmid3008716">{{cite journal | vauthors = Marcus F, Gontero B, Harrsch PB, Rittenhouse J | title = Amino acid sequence homology among fructose-1,6-bisphosphatases | journal = Biochemical and Biophysical Research Communications | volume = 135 | issue = 2 | pages = 374–81 | date = Mar 1986 | pmid = 3008716 | doi = 10.1016/0006-291X(86)90005-7 | bibcode = 1986BBRC..135..374M }}</ref>

:<small>D</small>-fructose 1,6-bisphosphate + H<sub>2</sub>O = <small>D</small>-fructose 6-phosphate + phosphate

[[Phosphofructokinase]] (EC	2.7.1.11) catalyses the reverse conversion of fructose 6-phosphate to fructose-1,6-bisphosphate, but this is not just the reverse reaction, because the co-substrates are different (and so thermodynamic requirements are not violated). The two enzymes each catalyse the conversion in one direction only, and are regulated by metabolites such as [[fructose 2,6-bisphosphate]] so that high activity of one of them is accompanied by low activity of the other. More specifically, fructose 2,6-bisphosphate allosterically inhibits fructose 1,6-bisphosphatase, but activates phosphofructokinase-I. Fructose 1,6-bisphosphatase is involved in many different [[metabolism|metabolic pathways]] and found in most [[organism]]s. FBPase requires metal [[ion]]s for catalysis ([[Magnesium|Mg]]<sup>2+</sup> and [[Manganese|Mn]]<sup>2+</sup> being preferred) and the enzyme is potently inhibited by [[Lithium|Li]]<sup>+</sup>.

== Structure ==

The [[protein folding|fold]] of fructose-1,6-bisphosphatase from [[pigs]] was noted to be identical to that of inositol-1-phosphatase (IMPase).<ref name="pmid8382485">{{cite journal | vauthors = Zhang Y, Liang JY, Lipscomb WN | title = Structural similarities between fructose-1,6-bisphosphatase and inositol monophosphatase | journal = Biochemical and Biophysical Research Communications | volume = 190 | issue = 3 | pages = 1080–3 | date = Feb 1993 | pmid = 8382485 | doi = 10.1006/bbrc.1993.1159 | bibcode = 1993BBRC..190.1080Z }}</ref> [[Inositol]] polyphosphate 1-phosphatase (IPPase), IMPase and FBPase share a [[sequence motif]] ([[Aspartic acid|Asp]]-[[Proline|Pro]]-[[Isoleucine|Ile]]/[[Leucine|Leu]]-Asp-[[Glycine|Gly]]/[[Serine|Ser]]-[[Threonine|Thr]]/Ser) which has been shown to [[Molecular binding|bind]] metal [[ions]] and participate in catalysis. This [[protein motif|motif]] is also found in the distantly-related [[fungal]], [[bacteria]]l and [[Saccharomyces cerevisiae|yeast]] IMPase [[Sequence homology|homologues]]. It has been suggested that these [[protein]]s define an ancient [[structurally]] conserved family involved in diverse [[metabolism|metabolic]] pathways, including inositol signalling, gluconeogenesis, sulphate assimilation and possibly [[quinone]] [[metabolism]].<ref name="pmid7761465">{{cite journal | vauthors = York JD, Ponder JW, Majerus PW | title = Definition of a metal-dependent/Li<sup>+</sup>-inhibited phosphomonoesterase protein family based upon a conserved three-dimensional core structure | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 92 | issue = 11 | pages = 5149–53 | date = May 1995 | pmid = 7761465 | pmc = 41866 | doi = 10.1073/pnas.92.11.5149 | bibcode = 1995PNAS...92.5149Y | doi-access = free }}</ref>

== Species distribution ==

Three different groups of FBPases have been identified in [[eukaryotes]] and [[bacteria]] (FBPase I-III).<ref name="pmid10986273">{{cite journal | vauthors = Donahue JL, Bownas JL, Niehaus WG, Larson TJ | title = Purification and characterization of glpX-encoded fructose 1, 6-bisphosphatase, a new enzyme of the glycerol 3-phosphate regulon of ''Escherichia coli'' | journal = Journal of Bacteriology | volume = 182 | issue = 19 | pages = 5624–7 | date = Oct 2000 | pmid = 10986273 | pmc = 111013 | doi = 10.1128/jb.182.19.5624-5627.2000 }}</ref> None of these groups have been found in [[Archaea]] so far, though a new group of FBPases (FBPase IV) which also show [[inositol monophosphatase]] activity has recently been identified in Archaea.<ref name="pmid11062561">{{cite journal | vauthors = Stec B, Yang H, Johnson KA, Chen L, Roberts MF | title = MJ0109 is an enzyme that is both an inositol monophosphatase and the 'missing' archaeal fructose-1,6-bisphosphatase | journal = Nature Structural Biology | volume = 7 | issue = 11 | pages = 1046–50 | date = Nov 2000 | pmid = 11062561 | doi = 10.1038/80968 | s2cid = 7617099 }}</ref>

A new group of FBPases (FBPase V) is found in [[thermophilic]] archaea and the hyperthermophilic [[bacterium]] ''[[Aquifex aeolicus]]''.<ref name="pmid12065581">{{cite journal | vauthors = Rashid N, Imanaka H, Kanai T, Fukui T, Atomi H, Imanaka T | title = A novel candidate for the true fructose-1,6-bisphosphatase in archaea | journal = The Journal of Biological Chemistry | volume = 277 | issue = 34 | pages = 30649–55 | date = Aug 2002 | pmid = 12065581 | doi = 10.1074/jbc.M202868200 | doi-access = free }}</ref> The characterised members of this group show strict [[substrate specificity]] for FBP and are suggested to be the true FBPase in these [[organism]]s.<ref name="pmid12065581"/><ref name="pmid15274916">{{cite journal | vauthors = Nishimasu H, Fushinobu S, Shoun H, Wakagi T | title = The first crystal structure of the novel class of fructose-1,6-bisphosphatase present in thermophilic archaea | journal = Structure | volume = 12 | issue = 6 | pages = 949–59 | date = Jun 2004 | pmid = 15274916 | doi = 10.1016/j.str.2004.03.026 | doi-access = free }}</ref> A [[secondary structure|structural]] study suggests that FBPase V has a novel [[protein folding|fold]] for a [[sugar]] [[phosphatase]], forming a four-layer alpha-beta-beta-alpha sandwich, unlike the more usual five-layered alpha-beta-alpha-beta-alpha arrangement.<ref name="pmid15274916"/> The arrangement of the [[catalytic]] [[side chain]]s and metal [[ligands]] was found to be consistent with the three-metal [[ion]] assisted catalysis mechanism proposed for other FBPases.

The fructose 1,6-bisphosphatases found within the ''[[Bacillota]]'' (low GC [[Gram-positive]] bacteria) do not show any significant [[sequence (biology)|sequence]] similarity to the [[enzymes]] from other [[organism]]s. The ''[[Bacillus subtilis]]'' enzyme is inhibited by [[Adenosine monophosphate|AMP]], though this can be overcome by [[phosphoenolpyruvate]], and is dependent on Mn(2+).<ref name="pmid221467">{{cite journal | vauthors = Fujita Y, Freese E | title = Purification and properties of fructose-1,6-bisphosphatase of Bacillus subtilis | journal = The Journal of Biological Chemistry | volume = 254 | issue = 12 | pages = 5340–9 | date = Jun 1979 | doi = 10.1016/S0021-9258(18)50601-3 | pmid = 221467 | doi-access = free }}</ref><ref name="pmid9696785">{{cite journal | vauthors = Fujita Y, Yoshida K, Miwa Y, Yanai N, Nagakawa E, Kasahara Y | title = Identification and expression of the Bacillus subtilis fructose-1, 6-bisphosphatase gene (fbp) | journal = Journal of Bacteriology | volume = 180 | issue = 16 | pages = 4309–13 | date = Aug 1998 | pmid = 9696785 | pmc = 107433 | doi =  10.1128/JB.180.16.4309-4313.1998}}</ref> [[Mutant]]s lacking this enzyme are apparently still able to grow on gluconeogenic growth substrates such as [[malate]] and [[glycerol]].

<gallery>
 Image:Beta-D-fructose-1,6-bisphosphate wpmp.png |[[Fructose 1,6-bisphosphate]]
 Image:Beta-D-fructose-6-phosphate wpmp.png |[[Fructose 6-phosphate]]
</gallery>

==Interactive pathway map==
{{GlycolysisGluconeogenesis_WP534|highlight=Fructose_1,6-bisphosphatase}}

==Hibernation and cold adaptation==

Fructose 1,6-bisphosphatase also plays a key role in [[hibernation]], which requires strict regulation of [[Metabolism|metabolic]] processes to facilitate entry into hibernation, maintenance, arousal from hibernation, and adjustments to allow long-term [[dormancy]].<ref name="Storey_1997">{{cite journal | vauthors = Storey KB | title = Metabolic regulation in mammalian hibernation: enzyme and protein adaptations | journal = Comparative Biochemistry and Physiology A | volume = 118 | issue = 4 | pages = 1115–24 | date = December 1997 | pmid = 9505421 | doi = 10.1016/S0300-9629(97)00238-7 }}</ref><ref name="Heldmaier_2004">{{cite journal | vauthors = Heldmaier G, Ortmann S, Elvert R | title = Natural hypometabolism during hibernation and daily torpor in mammals | journal = Respiratory Physiology & Neurobiology | volume = 141 | issue = 3 | pages = 317–29 | date = August 2004 | pmid = 15288602 | doi = 10.1016/j.resp.2004.03.014 | s2cid = 32940046 }}</ref><ref name = "Brooks_1992">{{cite journal | last1 = Brooks | first1 = Stephen P.J. | last2 = Storey | first2 = Kenneth B. | title = Mechanisms of glycolytic control during hibernation in the ground squirrel Spermophilus lateralis | journal = Journal of Comparative Physiology B | date = January 1992 | volume = 162 | issue = 1 | pages = 23–28 | doi = 10.1007/BF00257932 | s2cid = 1881399 }}</ref> During hibernation, an animal's metabolic rate may decrease to around 1/25 of its [[euthermic]] resting metabolic rate.<ref name="Heldmaier_2004" /><ref name="Brooks_1992" /><ref name="MacDonald_2002">{{cite journal | vauthors = MacDonald JA, Storey KB | title = Purification and characterization of fructose bisphosphate aldolase from the ground squirrel, Spermophilus lateralis: enzyme role in mammalian hibernation | journal = Archives of Biochemistry and Biophysics | volume = 408 | issue = 2 | pages = 279–85 | date = December 2002 | pmid = 12464282 | doi = 10.1016/S0003-9861(02)00579-9 }}</ref> FBPase is modified in hibernating animals to be much more temperature sensitive than it is in euthermic animals.<ref name="Storey_1997" /><ref name="Brooks_1992" /><ref name="MacDonald_2002" /> FBPase in the liver of a hibernating bat showed a 75% decrease in K<sub>m</sub> for its substrate FBP at 5&nbsp;°C than at 37&nbsp;°C.<ref name="Storey_1997" /> However, in a euthermic bat this decrease was only 25%, demonstrating the difference in temperature sensitivity between hibernating and euthermic bats.<ref name="Storey_1997" /> When sensitivity to [[Allosteric regulation|allosteric]] inhibitors such as [[Adenosine monophosphate|AMP]], ADP, inorganic phosphate, and [[Fructose 2,6-bisphosphate|fructose-2,6-bisphosphate]] were examined, FBPase from hibernating bats was much more sensitive to inhibitors at low temperature than in euthermic bats.<ref name="Storey_1997" /><ref name="Ekdahl_1984">{{cite journal | vauthors = Ekdahl KN, Ekman P | title = The effect of fructose 2,6-bisphosphate and AMP on the activity of phosphorylated and unphosphorylated fructose-1,6-bisphosphatase from rat liver | journal = FEBS Letters | volume = 167 | issue = 2 | pages = 203–9 | date = February 1984 | pmid = 6321241 | doi =10.1016/0014-5793(84)80127-1 | bibcode = 1984FEBSL.167..203N | s2cid = 22515761 }}</ref><ref name="Taketa_1965">{{cite journal | vauthors = Taketa K, Pogell BM | title = Allosteric Inhibition of Rat Liver Fructose 1,6-Diphosphatase by Adenosine 5'-Monophosphate | journal = The Journal of Biological Chemistry | volume = 240 | pages = 651–62 | date = February 1965 | issue = 2 | doi = 10.1016/S0021-9258(17)45224-0 | pmid = 14275118 | doi-access = free }}</ref>

During hibernation, respiration also dramatically decreases, resulting in conditions of relative [[Hypoxia (medical)|anoxia]] in the tissues. Anoxic conditions inhibit [[gluconeogenesis]], and therefore FBPase, while stimulating [[glycolysis]], and this is another reason for reduced FBPase activity in hibernating animals.<ref name="Underwood_1967">{{cite journal | vauthors = Underwood AH, Newsholme EA | title = Control of glycolysis and gluconeogenesis in rat kidney cortex slices | journal = The Biochemical Journal | volume = 104 | issue = 1 | pages = 300–5 | date = July 1967 | pmid = 4292000 | pmc = 1270577 | doi = 10.1042/bj1040300}}</ref> The substrate of FBPase, fructose 1,6-bisphosphate, has also been shown to activate [[pyruvate kinase]] in glycolysis, linking increased glycolysis to decreased gluconeogenesis when FBPase activity is decreased during hibernation.<ref name="Brooks_1992" />

In addition to hibernation, there is evidence that FBPase activity varies significantly between warm and cold seasons even for animals that do not hibernate.<ref name="Fischer_1974">{{cite book | veditors = Fischer EH, Krebs EG, Neurath H, Stadtman ER | title = Metabolic Interconversion of Enzymes 1973 Third International Symposium held in Seattle, June 5-8, 1973 | date = 1974 | publisher = Springer | location = Berlin, Heidelberg | isbn = 978-3-642-80817-3 }}</ref>
In rabbits exposed to cold temperatures, FBPase activity decreased throughout the duration of cold exposure, increasing when temperatures became warmer again.<ref name="Fischer_1974" /> The mechanism of this FBPase inhibition is thought to be digestion of FBPase by [[Lysosome|lysosomal]] [[protease]]s, which are released at higher levels during colder periods.<ref name="Fischer_1974" /> Inhibition of FBPase through [[proteolytic]] digestion decreases gluconeogenesis relative to glycolysis during cold periods, similar to hibernation.<ref name="Fischer_1974" />

Fructose 1,6-bisphosphate aldolase is another temperature dependent enzyme that plays an important role in the regulation of glycolysis and gluconeogenesis during hibernation.<ref name="MacDonald_2002" /> Its main role is in glycolysis instead of gluconeogenesis, but its [[substrate (biochemistry)|substrate]] is the same as FBPase's, so its activity affects that of FBPase in gluconeogenesis. [[Aldolase]] shows similar changes in activity to FBPase at colder temperatures, such as an upward shift in optimum pH at colder temperatures. This adaptation allows enzymes such as FBPase and fructose-1,6-bisphosphate aldolase to track intracellular pH changes in hibernating animals and match their activity ranges to these shifts.<ref name="MacDonald_2002" /> Aldolase also complements the activity of FBPase in anoxic conditions (discussed above) by increasing glycolytic output while FBPase inhibition decreases gluconeogenesis activity.<ref name="Dawson_2013">{{cite journal | vauthors = Dawson NJ, Biggar KK, Storey KB | title = Characterization of fructose-1,6-bisphosphate aldolase during anoxia in the tolerant turtle, ''Trachemys scripta elegans'': an assessment of enzyme activity, expression and structure | journal = PLOS ONE | volume = 8 | issue = 7 | article-number = e68830 | date = 2013 | pmid = 23874782 | pmc = 3715522 | doi = 10.1371/journal.pone.0068830 | bibcode = 2013PLoSO...868830D | doi-access = free }}</ref>

==Diabetes==
[[File:Adenosine monophosphate molecular diagram.jpg|thumb|baseline|AMP]]

Fructose 1,6-bisphosphatase is also a key player in treating [[Diabetes mellitus type 2|type 2 diabetes]]. In this disease, [[hyperglycemia]] causes many serious problems, and treatments often focus on lowering blood sugar levels.<ref name="Dang_2012">{{cite book | first1 = Qun | last1 = Dang | first2 = Paul D. | last2 = Van Poelje | first3 = Mark D. | last3 = Erion | editor-last1 = Jones | editor-first1 = Robert M. | chapter = Chapter 11: The Discovery and Development of MB07803, a Second-Generation Fructose-1,6-bisphosphatase Inhibitor with Improved Pharmacokinetic Properties, as a Potential Treatment of Type 2 Diabetes | title = New Therapeutic Strategies for Type 2 Diabetes: Small Molecule Approaches | date = 2012 | publisher = The Royal Society of Chemistry | location = Cambridge | isbn = 978-1-84973-414-1 | doi = 10.1039/9781849735322-00306 | doi-broken-date = 6 July 2025 }}</ref><ref name="Arch_2011">{{cite book | first = Jonathan R. S. | last = Arch | editor-last1 = Schwanstecher | editor-first1 = Mathias | title = Diabetes - Perspectives in Drug Therapy | chapter = Thermogenesis and Related Metabolic Targets in Anti-Diabetic Therapy | date = 2011  | publisher = Springer | location = Berlin, Heidelberg | isbn = 978-3-642-17214-4 | edition = 1st | page = 203 }}</ref><ref name="van_Poelje_2006">{{cite journal | vauthors = van Poelje PD, Potter SC, Chandramouli VC, Landau BR, Dang Q, Erion MD | title = Inhibition of fructose 1,6-bisphosphatase reduces excessive endogenous glucose production and attenuates hyperglycemia in Zucker diabetic fatty rats | journal = Diabetes | volume = 55 | issue = 6 | pages = 1747–54 | date = June 2006 | pmid = 16731838 | doi = 10.2337/db05-1443 | s2cid = 19832318 | doi-access =  }}</ref> Gluconeogenesis in the liver is a major cause of glucose overproduction in these patients, and so inhibition of gluconeogenesis is a reasonable way to treat type 2 diabetes. FBPase is a good enzyme to target in the gluconeogenesis pathway because it is rate-limiting and controls the incorporation of all three-carbon substrates into glucose but is not involved in glycogen breakdown and is removed from mitochondrial steps in the pathway.<ref name="Dang_2012" /><ref name="Arch_2011" /><ref name="van_Poelje_2006" /> This means that altering its activity can have a large effect on gluconeogenesis while reducing the risk of [[hypoglycemia]] and other potential side effects from altering other enzymes in gluconeogenesis.<ref name="Dang_2012" /><ref name="Arch_2011" />

Drug candidates have been developed that mimic the inhibitory activity of AMP on FBPase.<ref name="Dang_2012" /><ref name="van_Poelje_2006" /> Efforts were made to mimic the allosteric inhibitory effects of AMP while making the drug as structurally different from it as possible.<ref name="van_Poelje_2006" /> Second-generation FBPase inhibitors have now been developed and have had good results in clinical trials with non-human mammals and now humans.<ref name="Dang_2012" /><ref name="pmid29055870">{{cite journal | vauthors = Kaur R, Dahiya L, Kumar M | title = Fructose-1,6-bisphosphatase inhibitors: A new valid approach for management of type 2 diabetes mellitus | journal = European Journal of Medicinal Chemistry | volume = 141 | pages = 473–505 | date = December 2017 | pmid = 29055870 | doi = 10.1016/j.ejmech.2017.09.029 }}</ref>

== See also ==
*[[Fructose bisphosphatase deficiency]]
*[[Fructose]]
*[[Gluconeogenesis]]
*[[Metabolism]]

== References ==
{{reflist|33em}}

== Further reading ==
* {{cite book | first1 = Jeremy Mark | last1 = Berg | first2 = John L. | last2 = Tymoczko | first3 = Lubert | last3 = Stryer | year = 2002 | title = Biochemistry | chapter = Glycolysis and Gluconeogenesis | editor = Susan Moran | edition = 5th | publisher = W. H. Freeman and Company | location = New York| isbn = 0-7167-3051-0 | url = https://archive.org/details/biochemistrychap00jere | url-access = registration }}

== External links ==
* {{MeshName|Fructose-1,6-Biphosphatase}}

{{InterPro content|IPR000146}}

{{InterPro content|IPR009164}}

{{InterPro content|IPR002803}}

{{Glycolysis enzymes}}
{{Esterases}}
{{Enzymes}}
{{Portal bar|Biology|border=no}}

[[Category:EC 3.1.3]]
[[Category:Protein families]]